First 'non-gene' mutations behind neurodevelopmental disorders discovered

The study is a positive step towards providing an explanation for children with undiagnosed neurodevelopmental disorders

First 'non-gene' mutations behind neurodevelopmental disorders discovered

First 'non-gene' mutations behind neurodevelopmental disorders found, as part of the Deciphering Developmental Disorders (DDD) project
The study of almost 8,000 families, published in Nature, has found for the first time that mutations outside of genes can cause rare developmental disorders of the central nervous system

In the largest study of its kind, genetic changes causing neurodevelopmental disorders have been discovered by scientists at the Wellcome Sanger Institute and their collaborators in the NHS Regional Genetics services. The study of almost 8,000 families, published today (21 March) in Nature, found for the first time that mutations outside of genes can cause rare developmental disorders of the central nervous system.

The study is a positive step towards providing an explanation for children with undiagnosed neurodevelopmental disorders.

Every year in the UK, thousands of babies are born with errors in their DNA that mean they do not develop normally. These genetic changes, or mutations, can lead to conditions such as intellectual disability, epilepsy, autism or heart defects.

Due to their rarity, many of these developmental disorders remain undiagnosed. In 2010 the Deciphering Developmental Disorders (DDD) study was established to find diagnoses for children with unknown developmental diseases using genomics.

So far, around one third of the over 13,000 children in the DDD study have been diagnosed, but two thirds of the families still don’t have answers.

In the latest study, researchers investigated genetic disorders of the central nervous system, such as developmental brain dysfunction that can lead to impaired learning and language.

The team studied the genomes of almost 8,000 child and parent trios, focusing on genes that coded for proteins as well as non-coding parts of the genome that control the switching on and off of genes, known as regulatory elements.

Researchers discovered that mutations outside of genes, in regulatory elements, can cause these neurodevelopmental disorders. These regulatory elements have been very highly conserved over mammalian evolutionary history, suggesting that they have a critical role in early brain development.

“For the first time, we’ve been able to say how many children with severe neurodevelopmental disorders have damaging genetic changes in parts of the genome called regulatory elements. Of the near 8,000 families we studied, up to 140 children are likely to have these particular mutations that are responsible for their condition. We’re getting closer to providing a diagnosis for these families.”

Patrick Short, first author from the Wellcome Sanger Institute

To understand the mechanism by which these mutations can cause neurodevelopmental disorders, the mutated regulatory elements must be linked to the genes they target. This can be challenging, as genes and the elements that regulate their expression are often located far apart in the genome.

“In order to be able to give a genetic diagnosis for these children with neurodevelopmental disorders, we must first associate individual regulatory elements with specific disorders. This will be made possible, in part, by involving larger numbers of families in our studies. Data from the NHS 100,000 Genomes Project, being delivered by Genomics England, could be crucial in providing additional evidence to allow us to define these disorders with sufficient precision to allow diagnoses to be made.”

Dr Matthew Hurles, leader of the DDD Study and lead author from the Wellcome Sanger Institute

“This study is a promising step towards providing the answers that families have been seeking for years. Once these families receive a diagnosis, they will be able to make decisions about the treatment options for their child and make future plans for their family.”

Professor Anneke Lucassen, chair of the British Society of Genetic Medicine

Notes to Editors

Short P et al. (2018) De novo mutations in regulatory elements in neurodevelopmental disorders. Nature. DOI: 10.1038/nature25983


This work was supported by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between Wellcome and the UK Department of Health, the Wellcome Sanger Institute (grant WT098051), and the MRC Human Genetics Unit programme.

Selected Websites
What is a genetic disorder?FactsWhat is a genetic disorder?
A genetic disorder is a disease that is caused by a change, or mutation, in an individual’s DNA sequence.

What is genetic variation?FactsWhat is genetic variation?
Genetic variation is a term used to describe the variation in the DNA sequence in each of our genomes. Genetic variation is what makes us all unique, whether in terms of hair colour, skin colour or even the shape of our faces. 

What is a chromosome disorder?FactsWhat is a chromosome disorder?
A chromosome disorder results from a change in the number or structure of chromosomes.  

What is a mutation?FactsWhat is a mutation?
A mutation is a change that occurs in our DNA sequence, either due to mistakes when the DNA is copied or as the result of environmental factors such as UV light and cigarette smoke. 

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